ABSTRACT The hallmark neuropathologic lesions of Alzheimer's disease (AD) are amyloid-beta (A?) and tau deposits. These deposits can be observed in clinically normal adults, on average 20 years before the onset of cognitive impairment. Despite considerable advance in imaging and biomarkers, researchers are not yet able to identify individuals expected to accumulate pathology prior to showing any pathology. As clinical trials are moving to earlier intervention a more accurate selection of participants at risk for accumulating AD pathology will be crucial. The overarching goal of this proposal is to evaluate in vivo locus coeruleus (LC) integrity as a gauge discerning cognitive aging from preclinical AD based on its very early associations with A?, tau accumulation patterns and trajectories of cognitive decline. The overall scientific premise for our goal is that autopsy studies indicated that the first tau lesions can be detected in the LC in 80% of the 40-year old cases, and LC integrity correlates with cognition, even in persons with no pathology. The recent development of tau tracers and novel methods to visualize the LC in detail provide now the opportunity to investigate associations between LC integrity, age, A?, tau and cognition. The central hypothesis is that LC integrity can predict regional tau accumulations and cognitive decline in individuals with lower levels of A?, already at midlife. Serial A? and tau PET measures, serial 3T MRI, serial cognitive assessments and dedicated baseline 7T LC-MRI scans will be collected in individuals between 36-56 years old carefully selected from the Human Connectome Project. This data will be leveraged to another longitudinal cohort, the Harvard Aging Brain Study and our existing patient studies. Three specific areas that could potentially identify individuals on a trajectory to preclinical AD will be addressed: 1) to identify cross-sectional associations between age, sex and LC integrity for individuals at different stages of A? and tau pathology and different cognitive impairment levels, which will contribute to the assessment of LC integrity as a biomarker for AD pathology (Aim 1); 2) the quantification of the range of LC integrity levels that predict regional tau accumulation and memory decline in clinically normal individuals, which will elucidate the spatial tau patterns associated with LC integrity and may help in discerning individuals on a trajectory of cognitive aging versus those towards preclinical AD (Aim 2); 3) to investigate underlying mechanisms of spread of pathology by relating structural connectivity and functional activity during a sensitive memory task to rates of tau accumulation (Aim 3). The research proposed in this application is innovative because it moves early detection to a younger adult group (<60 years), which will provide information on the role of LC integrity in preclinical AD and in cognitive aging. In addition, establishing potential mechanisms of pathology progression will be relevant for the development of new pharmaceuticals. Ultimately, being able to discern normal age-related from AD-related trajectories has a significant potential to move early detection and intervention to time frames where A? is low or not yet detectable, rendering preventive trials more successful.